sirolimus and Endometrial-Hyperplasia

Adenomyosis, endometriosis, endometritis, and typical endometrial hyperplasia are common non-cancerous diseases of the endometrium that afflict many women with life-impacting consequences. The mammalian target of the rapamycin (mTOR) pathway interacts with estrogen signaling and is known to be dysregulated in endometrial cancer. Based on this knowledge, we attempt to investigate the role of mTOR signaling in benign endometrial diseases while focusing on how the interplay between mTOR and eukaryotic translation initiation factors (eIFs) affects their development. In fact, mTOR overactivity is apparent in adenomyosis, endometriosis, and typical endometrial hyperplasia, where it promotes endometrial cell proliferation and invasiveness. Recent data show aberrant expression of various components of the mTOR pathway in both eutopic and ectopic endometrium of patients with adenomyosis or endometriosis and in hyperplastic endometrium as well. Moreover, studies on endometritis show that derangement of mTOR signaling is linked to the establishment of endometrial dysfunction caused by chronic inflammation. This review shows that inhibition of the mTOR pathway has a promising therapeutic effect in benign endometrial conditions, concluding that mTOR signaling dysregulation plays a critical part in their pathogenesis.

Topics: Adenomyosis; Endometrial Hyperplasia; Endometriosis; Endometritis; Endometrium; Female; Humans; Sirolimus; TOR Serine-Threonine Kinases; Uterine Diseases

During aging, uncontrolled epithelial cell proliferation in the uterus results in endometrial hyperplasia and/or cancer development. The mTOR signaling pathway is one of the major regulators of aging as suppression of this pathway prolongs lifespan in model organisms. Genetic alterations in this pathway via mutations and/or amplifications are often encountered in endometrial cancers. However, the exact contribution of mTOR signaling and uterine aging to endometrial pathologies is currently unclear. This study examined the role of mTOR signaling in uterine aging and its implications in the development of endometrial hyperplasia. The hyperplastic endometrium of both postmenopausal women and aged mice exhibited elevated mTOR activity as seen with increased expression of the pS6 protein. Analysis of uteri from Pten heterozygous and Pten overexpressing mice further confirmed that over-activation of mTOR signaling leads to endometrial hyperplasia. Pharmacological inhibition of mTOR signaling using rapamycin treatment suppressed endometrial hyperplasia in aged mice. Furthermore, treatment with mTOR inhibitors reduced colony size and proliferation of a PTEN negative endometrial cancer cell line in 3D culture. Collectively, this study suggests that hyperactivation of the mTOR pathway is involved in the development of endometrial hyperplasia in aged women and mice.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Endometrial Hyperplasia; Endometrial Neoplasms; Endometrium; Epithelial Cells; Female; Genetic Predisposition to Disease; Humans; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Protein Kinase Inhibitors; PTEN Phosphohydrolase; Signal Transduction; Sirolimus; Spheroids, Cellular; TOR Serine-Threonine Kinases

The mechanism of tamoxifen-associated endometrial hyperplasia and cancer is not elicited. RAD001 inhibits a target protein in phosphatidyl kinase pathway, which is involved in endometrial hyperplasia and cancer. We investigated whether endometrial hyperplasia can be prevented through inhibition of the target of rapamycin by RAD001. Sixty BALB/c mice underwent oophorectomy and were divided into 6 groups: group 1, placebo group; group 2, tamoxifen-treated (4 mg/kg per 24 hours); group 3, estradiol-treated (4 mg/kg per 24 hours); group 4, RAD001-treated (1.5 mg/kg per 24 hours); group 5, tamoxifen (4 mg/kg per 24 hours)-and-RAD001 (1.5 mg/kg per 24 hours)-treated; and group 6, estradiol (4 mg/kg per 24 hours)-and-RAD001 (1.5 mg/kg per 24 hours)-treated. The count of glands, the length of epithelium, and immunohistochemical staining of proliferating cell nuclear antigen were analyzed. The count of total glands and the epithelial length were 30.8 (7.1) and 126 (43.4) microm, 53 (8.1) and 162.5 (34.8) microm, 65.2 (13.6) and 401.4 (44.0) microm, and 82.0 (5.2) and 444.7 (57.8) microm in the placebo-, the RAD001-, the tamoxifen-, and the estradiol-treated groups, respectively (P < 0.05). Although addition of RAD001 to estradiol did not decrease the count of total glands and the epithelial length, addition of RAD001 to tamoxifen did (43.3 [13.3] and 218.0 [29.2] microm, P < 0.05). The immunoreactive score of proliferating cell nuclear antigen is significantly decreased by the addition of RAD001 to either tamoxifen or estradiol in the epithelial and glandular cells. RAD001 can prevent tamoxifen-associated and estrogen-related endometrial hyperplasias in mice. RAD001 also decreases stromal cell proliferation in the tamoxifen-treated mice.

Topics: Animals; Antineoplastic Agents, Hormonal; Carrier Proteins; Cell Proliferation; Endometrial Hyperplasia; Endometrial Neoplasms; Estradiol; Estrogens; Everolimus; Female; Immunoenzyme Techniques; Immunosuppressive Agents; Mice; Mice, Inbred BALB C; Ovariectomy; Phosphotransferases (Alcohol Group Acceptor); Sirolimus; Stromal Cells; Survival Rate; Tamoxifen; TOR Serine-Threonine Kinases; Treatment Outcome

Phosphatase and tensin homolog (PTEN) mutations are associated with human endometrial cancers, and PTEN heterozygote(+/-) mice have a high rate of endometrial neoplasia. The objective of this study was to evaluate an oral mTOR inhibitor (mTOR-I) on the reduction of endometrial hyperplasia in an animal model.. Three groups of 10 female mice were treated from age 20-26 weeks: group A, Pten wild type with mTOR-I; group B, Pten+/- with placebo; and group C, Pten +/- with mTOR-I. Rates of hyperplasia and markers of proliferation and apoptosis were evaluated.. Higher grade hyperplasia occurred in a significantly greater percentage of the untreated Pten+/- group B (80%; 8/10) compared with groups A (0%; 0/10) and C (20%; 2/10; P < .02). The treated Pten+/- mTOR-I group C also demonstrated significantly increased apoptosis (P < .002) and decreased proliferation index (P < .02) compared with the untreated group B.. Oral mTOR inhibition decreases the progression of endometrial hyperplasia in the Pten heterozygote murine model through decreased cell proliferation and increased apoptosis.

Topics: Administration, Oral; Animals; Disease Progression; Endometrial Hyperplasia; Everolimus; Female; Heterozygote; Mice; Mice, Inbred C57BL; Mutation; Protein Kinases; PTEN Phosphohydrolase; Sirolimus; TOR Serine-Threonine Kinases

Amplified in breast cancer 1 (AIB1), an estrogen receptor (ER) coactivator, is frequently amplified or overexpressed in human breast cancer. We previously developed a transgenic mouse model in which AIB1 can act as an oncogene, giving rise to a premalignant hyperplastic mammary phenotype as well as to a high incidence of mammary tumors that are primarily ER(+). In this model, the AIB1 transgene is responsible for continued activation of the insulin-like growth factor-I receptor, suggesting a role for the activation of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway in the premalignant phenotype and tumor development. Here we show that treatment of AIB1 transgenic mice with the mTOR inhibitor RAD001 reverts the premalignant phenotype. Furthermore, treatment of cell lines derived from AIB1-dependent mammary tumors with RAD001 in culture leads to a G(1) cell cycle arrest. Lastly, tumor growth after injection of ER(+) AIB1 tumor cell lines into wild-type animals is inhibited by RAD001 treatment. In this ER(+) model, inhibition of tumor growth by RAD001 was significantly better than inhibition by the antiestrogen 4-hydroxytamoxifen alone, whereas a combination of both RAD001 and 4-hydroxytamoxifen was most effective. Based on these results, we propose that the combination of mTOR inhibition and ER-targeted endocrine therapy may improve the outcome of the subset of ER(+) breast cancers overexpressing AIB1. These studies provide preclinical support for the clinical development of RAD001 and suggest that AIB1 may be a predictive factor of RAD001 response.

Topics: Animals; Blotting, Western; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Endometrial Hyperplasia; Estrogen Receptor alpha; Everolimus; Female; G1 Phase; Histone Acetyltransferases; Immunohistochemistry; Immunosuppressive Agents; Mammary Neoplasms, Experimental; Mice; Mice, Transgenic; Nuclear Receptor Coactivator 3; Oncogenes; Precancerous Conditions; Protein Kinases; Receptors, Estrogen; Sirolimus; Tamoxifen; TOR Serine-Threonine Kinases; Trans-Activators; Tumor Cells, Cultured